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Solving the Food-Body Problem (continued)

In this clinical context, Dr. King was inspired to earn a doctorate in nutrition. In graduate school she studied protein requirements in pregnant women. “At the time there were two extremes: people who believed that a pregnant woman must eat for two, and others who maintained that her nutritional needs were not different than in her non-pregnant state,” Dr. King explains. She studied protein requirements in pregnant teens, hypothesizing they would be different from that of pregnant adults. In fact, they were very similar, possibly due to the fact that most study participants had begun menstruating more than two years prior to the study, so hormonally they were quite mature.

In 1990, Dr. King chaired an Institute of Medicine Committee charged with determining how much weight women should gain during pregnancy in order to give birth to a child of healthy weight—between three and three and a half kilos (or six and a half to seven and a half pounds). The rule of thumb then was to limit weight gain to no more than 25 pounds. But data available to the Committee indicated that weight gain depends on the mother’s weight at conception. So, different criteria were developed for women who were underweight, “ideal,” moderately overweight, and obese.

Through her research, Dr. King realized that “the ideal average woman” could gain anywhere between 10 and 50 pounds during pregnancy. “We still don’t understand the source of this variation and I think we need genetic information to explain it,” Dr. King says.

What Dr. King did understand was that not all women who accumulated additional calories, or fat stores, during pregnancy ate much more than their peers. Maternal fat gain seemed to relate to women’s basal metabolic rates (BMR), or the energy the body needs while at rest. Women with bigger babies had higher BMRs and gained less fat. It also turned out that basal metabolic rates were highest among pregnant obese women, which explained why they didn’t gain much weight during pregnancy.

Dr. King’s findings of an association between body fat and BMR in obese pregnant women were counter to scientists’ previous assumptions. BMR is typically related to the amount of lean muscle tissue; the more muscular the person, the more energy her body needs. But Dr. King maintained that in pregnant obese women, BMR correlated with body fat. “It took us a long time to publish this paper. The reviewers told us we were crazy. We discovered later that obese people secreted higher amounts of leptin, an enzyme secreted by adipose (fatty) tissue, and leptin was associated with high BMR,” Dr. King reports.

Dr. King wondered why, given that they had such high energy needs and did not gain much weight, obese women still delivered large babies. The probable answer: Obese women have high levels of glucose, the “preferred fuel” of the fetus, which passes readily through the placenta. In order to use glucose, the fetus must produce insulin. Because insulin is also a growth hormone, the babies are born large. “But bigger is not always better,” Dr. King cautions. Mothers of large babies may develop gestational diabetes. It also appears that some kind of fetal imprinting affects the metabolism of the child, so these children are often overweight as teens and are at greater risk for developing type 2 diabetes.

Dr. King’s current studies focus on whether, through diet, glucose levels in obese pregnant women can be controlled to prevent excessive transfer to, and accelerated growth of, the fetus. Her hypothesis is that a diet high in complex carbohydrates, as opposed to simple sugars, will prevent an increase in glucose secretion after meals and the associated accelerated fetal growth.

Dr. King’s interest in zinc metabolism happened by chance. After graduating from University of California, Berkeley, Dr. King accepted a faculty position at her alma mater. “I had no idea what I was doing,” she chuckles, recalling her naiveté. “I had completed this one study and was all of a sudden expected to set up my own laboratory, supervise graduate students, publish articles, teach… Without the support of my faculty colleagues, it would have been suicidal.”

But soon after her appointment, Dr. King was offered both a gift and a challenge when Sheldon Margen, MD, then chair of Berkeley’s Department of Nutritional Sciences, received a grant to study trace elements in women taking oral contraceptives. Saying he had no time to do the study, he handed the grant over to Dr. King.

Measuring zinc in the body was a challenge, because zinc is virtually everywhere. “It is very easy to contaminate a sample,” Dr. King explains. “We had to work under tents and use plastic instead of glass.” Also, the concentrations in tissues were extremely low, requiring the development of new methods to accurately determine the zinc content of blood, stool, and urine samples. Dr. King discovered women on the pill had lower levels of zinc in their plasma and urine. “That wasn’t very interesting,” Dr. King says. But what was interesting was that this was the first study ever done on zinc metabolism in humans; all previous studies had been in experimental animals.

“I realized that measuring concentration of zinc was not going to get us too far,” Dr. King continues. She suggested using radioactive zinc to trace its metabolism. Using elements with low radioactivity was an accepted practice, but Dr. Margen was ethically opposed to giving radioactive elements to women of reproductive age. Dr. King says the experience made her much more cautious and thoughtful about her research methods throughout her career.

An alternative was to use stable isotopes of zinc, but neither Dr. King nor her colleagues had any idea how to do so; it had never been done before. “So one day I walked all the way up the hill—the space assignment reflected the academic hierarchy, with nutrition at the bottom and Physics at the top of the Berkeley campus—to meet a faculty member in Physics and one of his students who he said could help me.” Dr. King remembers. “I walked in the room and wanted to turn around and run. The grad student looked like an 18-year-old who had just jumped off his surfboard and flown up from L.A. I thought, ‘How can I explain to him that I want him to help me find stable isotopes of zinc in fecal samples collected from women on the pill?’ But I was wrong about Chris. He developed a neutron activation method for measuring just that.” The methodology developed from that study is now employed worldwide, rendering the use of radioactive elements unnecessary. Chris Caan, PhD, went on to study calcium metabolism in astronauts using stable isotopes and is now on the faculty of the University of California, San Francisco.
Armed with good methodology and using iron as a model of mineral metabolism, Dr. King thought all she needed to do was find a good biochemical marker of zinc deficiency so human deficiency could be diagnosed. “Boy, was I stupid,” she now says. “Zinc isn’t at all like iron.”

Six men were fed a zinc-free diet. After three weeks, two of them reported a severe acne problem. A third man had diarrhea, and a fourth complained of sore throat. Dr. King was shocked to discover their plasma levels of zinc had dropped alarmingly. Three days after resuming a regular diet, the men were symptom-free. “I was confused: while zinc in plasma dropped in a mere three weeks, enzymes that required zinc didn’t change much.”
Since then, Dr. King has discovered that people tend to sequester zinc in their muscles and bones, where 90 percent of the body’s zinc is found, while the remaining 10 percent, in the blood, drops rapidly. Dr. King suggested that because zinc is essential in cell division and DNA replication, the body hangs on to as much as possible to prevent problems much more serious than those caused by low zinc levels in plasma.
Dr. King now studies the factors affecting zinc utilization from diet. Pregnant women, for example, need more zinc and their bodies meet that need by increasing absorption. However, iron—a supplement prescribed for virtually all pregnant women—interferes with zinc utilization. One of Dr. King’s latest studies, the results of which are still unknown, focuses on how to give iron to women while avoiding interference with zinc utilization.
After earning her doctorate, Dr. King spent her career in an academic research setting. She says she is glad to be in a research institute associated with a free-standing hospital. “My work in a clinical environment was what prompted me to earn a PhD, so I’m excited to return to these roots.”

After a stellar career spanning 30-plus years, Dr. King maintains: “Talking about my research is always a humbling experience because I always feel like I’ve just wandered around science and haven’t done much.”

Dr. King is a professor of nutrition and internal medicine at the University of California, Davis; a professor of nutrition at the University of California, Berkeley; and a scientist at CHORI. She is a member of the National Academy of Science’s Institute of Medicine.

---Researcher Profile

Monday, May 16, 2011 11:33 PM

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